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​​​​​​​Pharmacokinetic Drug Interactions Are A Big Deal 

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The USMLE Insider lectures in Pharmacology and the course material for Pharmacology is the best material out there for mastery of medical pharmacology and therapeutics. We receive great compliments from medical school faculty and physicians for the impact this material has had on their students in the clinics. We give you a snapshot here to illustrate why our course has received widespread acclaim.

Pharmacokinetic drug interactions are so important for the USMLE, and much of it centers on the cytochrome P450 system. The CYP enzymes are usually considered the most important Phase I drug metabolizing enzymes and are responsible for the oxidative metabolism of over 90% of prescribed drugs. 

The inhibition of CYP enzymes by medicines may result in enhanced systemic exposure of drugs leading to increased toxicity, while induction of CYP enzymes could result in reduced drug concentrations leading to subtherapeutic plasma levels of the drugs with reduced drug efficacy or even treatment failure as possible clinical consequences. 

In the Table shown below, substrates are the drugs that are dependent on the CYP3A4 isoenzyme for their metabolism; inhibitors are the drugs that could block this isoenzyme and lead to enhanced systemic exposure of the substrates while inducers are drugs that could induce this isoenzyme and lead to reduced plasma concentrations of the substrates with potential for reduced drug efficacy.

 Drugs Related to CYP3A4
Substrates Inhibitors Inducers

Antidepressants:
Amitriptyline
Clomipramine
Imipramine
Venlafaxine
Mirtazapine
Nefazodone 
Trazodone
Sertraline
Citalopram
 

Antipsychotics:
Haloperidol
Risperidone
Pimozide
Aripiprazole 
Ziprasidone
Quetiapine

 

Opioids:
Codeine 
Buprenorphine
Fentanyl
Alfentanyl
Hydrocodone  
Tramadol (into inactive metabolite)

 

Macrolides:
Clarithromycin
Erythromycin  
Telithromycin

 

Calcium Channel Blockers:
Amlodipine
Felodipine
Nifedipine
Nisoldipine
Nitrendipine
Lercanidipine
Verapamil
Diltiazem

 

Benzodiazepines:
Alprazolam
Midazolam
Triazolam
Diazepam (to desmethyldiazepam)
 

Antihistamines:
Astemizole
Chlorpheniramine
Terfenadine 

 

Antiarrhythmics:
Quinidine
Amiodarone 

 

HIV Protease Inhibitors:

Indinavir
Ritonavir
Saquinavir
Nelfinavir

 

NNRTIs*:
Nevirapine
Efavirenz
Delaviridine
Etravirine
Doravirine
Rilpivirine
 

HCV Protease Inhibitors:Telaprevir
Boceprevir

 

Immunomodulators:
Cyclosporine
Tacrolimus (FK506)
Sirolimus

 

Prokinetics:
Cisapride

 

PDE-5 Inhibitors:
Sildenafil
Tadalafil
Vardenafil

 

Methylxanthines:
Caffeine
Theophylline

 

Antiemetics:
Aprepitant
Netupitant 
Rolapitant
Palonosetron

 

HMG CoA Reductase Inhibitors:
Atorvastatin
Lovastatin
Simvastatin
Cerivastatin

 

Sex Hormone Modulators:
Estradiol
Ethinylestradiol
Progesterone
Testosterone
Finasteride

 

Others:
Tamoxifen
Buspirone
Carbamazepine
Imatinib
Quinine
Vincristine
Warfarin

Antiretrovirals:
Indinavir
Nelfinavir
Ritonavir
Saquinavir
 

Macrolides:
Clarithromycin
Telithromycin
Erythromycin
Troleandomycin

 

Azole Antifungals:
Itraconazole
Ketoconazole
Fluconazole
Voriconazole

 

Calcium Channel Blockers:
Verapamil
Diltiazem

 

Proton Pump Inhibitors:
Esomeprazole
Omeprazole
Pantoprazole

 

Antiemetics:
Aprepitant  
Netupitant
Rolapitant

 

Others:
Nefazodone
Grapefruit juice
Suboxone
Cimetidine
Chloramphenicol
Amiodarone
Fluvoxamine


Antibiotics:
Rifampin
Rifabutin

 

Anticonvulsants:
Carbamazepine
Phenytoin
Phenobarbital
Primidone
Topiramate
Oxcarbazepine

 

NNRTIs:
Efavirenz
Nevirapine

Hypoglycemics:
Pioglitazone
Troglitazone

 

Others:
St. John's Wort
Capsaicin
Modafanil
Enzalutamide

*NNRTI = Non-nucleoside reverse transcriptase inhibitors; HCV = hepatitis C virus

For example, triazolam is metabolized by the CYP3A4 and is therefore susceptible to interactions with erythromycin and other agents that inhibit CYP3A4, such cimetidine, probenecid, and nefazodone. Using any of these agents concurrently with triazolam would affect triazolam's pharmacokinetics by decreasing its hepatic metabolism and thereby increasing its bioavailability, half-life, and duration of action.

Conversely, aprepitant and its prodrug, fosaprepitant, may reduce the efficacy of low-dose hormonal contraceptives (such as estradiol/levonorgestrel) during and for up to 28 days after treatment because of aprepitant induction of CYP3A4, the isoenzyme partially responsible for the metabolic clearance of contraceptive hormones. This concomitant therapy with aprepitant or fosaprepitant may increase the risk of breakthrough bleeding and unintended pregnancy.  

Obviously, the CYP3A4 isoenzyme is not the only microsomal drug-metabolizing enzyme that you have to know. There are several others, including CYP2B6, 2D6, 2C8, 2C9, 2C19, 1A2, and 2E1. And we at USMLE Insider Prep Course have created excellent Tables with the most important substrates, inhibitors, and inducers of these isoenzymes just as we have shown here for CYP3A4.

Some drugs are influenced by multiple CYP isoenzymes and are therefore susceptible to multiplicity of drug-drug interactions. For example, netupitant is metabolized mainly by CYP3A4, and to a lesser degree by CYP2C9 and CYP2D6. Palonosetron is metabolized mainly by CYP2D6, and to a lesser extent by CYP3A4 and CYP1A2. Warfarin exists as a racemic mixture of the R- and S-enantiomers, with the S-enantiomer having 2-5 times more anticoagulant activity than the R-enantiomer. Biotransformation of the S-enantiomer to an inactive metabolite occurs predominantly by means of hydroxylation by CYP2C9, whereas the R-enantiomer involves CYP2C19, CYP1A2, and CYP3A4. 

Furthermore, the intestinal/hepatic microsomal enzyme systems are not the only systems influencing elimination of drugs that you must be conversant with. Some drugs, such as digoxin, are substrates of P-glycoprotein (P-gp), and are susceptible to changes in pharmacokinetics due to drug interactions with P-gp inhibitors or inducers. Some drugs are both substrates of CYP isoenzymes and P-gp efflux transporter.

Some drugs are substrates of organic anion transporting polypeptide (OATP) 1B1 and breast cancer resistance protein (BCRP) transporters. Therefore, coadministration with inhibitors of these transporters, such as eluxadoline, may increase the plasma concentrations of drugs that are substrates of the OATP1B1 and/or BCRP transporters. The mechanism is decreased clearance due to inhibition of OATP1B1-mediated hepatic uptake and BCRP-mediated intestinal and hepatobiliary efflux by eluxadoline. The interaction has been demonstrated for rosuvastatin, a known substrate of both OATP 1B1 and BCRP.

Some drugs are substrates of the renal organic cationic transporter-2 [OCT2] protein, which is a common renal tubular transport system involved in the renal elimination of certain drugs. Potent inhibitors of OCT2, such as dolutegravir, ranolazine, vandetanib, and cimetidine may decrease the renal elimination of an OCT2 substrate such as metformin resulting in increased metformin plasma concentrations and an increased risk of lactic acidosis. 

Apart from the metabolic interactions, there are other mechanisms such as highly protein bound drugs displacing other agents from serum albumin or protein binding sites and influencing their systemic exposure. 

The Pharmacology module of The USMLE Insider review course for USMLE Step 1 includes a list of The Most Important Drug-Drug and Drug-Food Interactions that a clinician must know. That is a list of hundreds of drugs, but it has never overwhelmed anyone! We show the consequence of their coadministration, the mechanisms underpinning those interactions and the adjustments that must be made, whether to avoid usage, monitor closely, increase or decrease dosage, or whether it is contraindicated.

Of the many varieties of drug interactions, which occur when the disposition or actions of one drug are changed by another, only a few are serious or potentially fatal. Precipitant drugs are those which produce the interaction, and object drugs are those whose effects are changed. The interactions which are usually significant are those which alter the metabolism, involve renal excretion, or change the effects of the object drug, especially when the object drug has a low therapeutic index (cardiovascular drugs, anticoagulants, drugs acting on the brain, hypoglycemic drugs, hormones, and cytotoxic drugs).

Anyway, check out two of the USMLE questions we have prepared on these concepts. At USMLE Insider Prep Course, we stimulate your mind with challenging questions. Not only are our USMLE course notes one to die for, but we create the fertile atmosphere for your brilliant mind to flourish. We stimulate you to think critically and help you not only achieve the highest score on the USMLE but also to be a great clinician. Test yourself with this and let us see how you do. We will discuss the answer and offer explanations later. 

1.  A 67-year-old woman with a history of nonvalvular atrial fibrillation has been receiving dabigatran therapy for stroke prevention and systemic embolization. She has complications  related to type 2 diabetes mellitus; her medical record shows a CrCl <30 mL/min. Four months later the patient is diagnosed with another condition and is placed on pharmacotherapy. Two weeks after initiation of treatment, she presents with dyspepsia and serious gastrointestinal bleeding. Which of the following drugs did the patient most likely receive?

A. Carbamazepine
B. Hydrochlorothiazide
C. Lovastatin
D. Propranolol
E. Quinidine
F. Rifampin

2. A 62-year-old woman with chronic-thromboembolic pulmonary hypertension is taking roiciguat. A year later, the patient is diagnosed with psoriasis. Topical agents are found to be ineffective and the physician wants to prescribe an immunomodulator. Use of which of the following drugs should be avoided.

A. Adalimumab
B. Apremilast
C. Cyclosporine
D. Infliximab
E. Methotrexate
F. Secukinumab


 

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